Combination therapy for reducing the risks associated with cardiovascular disease

ABSTRACT

The present invention involves a combination therapy of administering a cholesterol reducing agent, such as a 3-hydroxy-3-methylglutaryl coenzyme a (HMG-CoA) reductase inhibitor and a platelet aggregation inhibitor for treating, preventing or reducing the risk of developing cardiovascular and cerebrovascular events and disorders in a mammal.

This Application claims priority under 35USC, 119 i.e. over provisionalapplication Ser. No. 60/026,581 filed Sep. 18, 1996 and is aPCT/US97/16388 filed Sep. 15, 1997.

FIELD OF THE INVENTION

The instant invention involves a combination therapy comprising theadministration of a cholesterol reducing agent such as a3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (orHMG-CoA RI) and a platelet aggregation inhibitor for treating,preventing and reducing the risk of developing cardiovascular andcerebrovascular events and disorders in a mammal.

BACKGROUND OF THE INVENTION

Platelet activation and aggregation are involved in unstable angina andacute myocardial infarction, in reocclusion following thrombolytictherapy and angioplasty, in transient ischemic attacks and in a varietyof other vaso-occlusive disorders. When a blood vessel is damaged eitherby acute intervention such as angioplasty, or more chronically by thepathophysiological processes of atherosclerosis, platelets are activatedto adhere to the disrupted surface and to each other. This activation,adherence and aggregation may lead to occlusive thrombus formation inthe lumen of the blood vessel.

Antiplatelet therapy has been used in a wide variety of cardiovasculardisease states and in conjunction with interventional therapy such ascoronary artery or peripheral bypass grafting, cardiac valvereplacement, and percutaneous transluminal coronary angioplasty (PTCA).Available drugs, such as aspirin and ticlopidine (TICLID®), have shownefficacy in syndromes involving vascular occlusion, presumably due tosustained inhibition of platelet function. However, the inhibitoryeffects of aspirin and ticlopidine are dependent upon the agonist whichactivates the platelet. For example, aspirin is effective in blockingplatelet aggregation induced by agonists such as collagen that aredependent upon the cylooxygenase pathway. It is, however, less effectiveagainst concentrations of thrombin which can act by cyclooxygenaseindependent pathways. Likewise, the inhibitory effects of ticlopidine,which inhibits ADP induced platelet aggregation, can be overcome bycombinations of agonists. Thus, an efficacious platelet aggregationtherapy that acts independently of the agonist and the pathwayactivating the platelet could be an important therapeutic advance givinggreater efficacy than aspirin or ticlopidine alone in a broader spectrumof thrombotic events.

Integrin Superfamily

The firm attachment of endothelial cells to the subendothelialextracellular matrix is mediated via CAMs, which serve as receptorsrecognizing an array of adhesive proteins in the extracellular matrix.These proteins include von Willebrand factor (vWf), fibronectin,vitronectin, thrombospondin, laminins, collagen fibrils, elastin,microfibrils of elastin, and glycosaminoglycans. Most of the matrixadhesive molecules are the ligands for integrin receptors expressed inendothelial cells.

Integrins constitute an extended family (“superfamily”) of membranereceptors interacting with adhesive proteins in plasma and extracellularmatrix and with other membrane receptors (counter-receptors). The name“integrin” implies that they integrate the ligands on the outside of thecell with the cytoskeletal apparatus in the inside of the cell. Integrinreceptors consist of a noncovalently linked Ca²⁺-dependent,heterodimeric glycoprotein complex composed of α and β subunits. Theeight known integrin β subunits give rise to eight families in which one“founder” β subunit forms heterodimers with different α subunits. Thereare at least 14 known α subunits. Receptors belonging to the β₁ and β₃families are expressed in endothelial cells. The β₁ family, also namedVery Late Antigens (VLA), is represented by the fibronectin receptor(α₅β₁, or VLA-5), the collagen receptor (α₂β₁, or VLA-2) and the lamininreceptor (α₆β₁), The β₃ family is represented by the vitronectinreceptor (α_(v)β₃), which is structurally similar (the same β₃ subunit)to the platelet integrin receptor for fibrinogen, glycoprotein (GP)IIb/IIIa complex (also referred to as α_(IIb)β₃). The functionaldifference between these two receptors is that the platelet receptorrecognizes the γ chain domain (HHLGGAKQAGDV) of human fibrinogen and theendothelial vitronectin receptor does not. Both recognize the sequenceR-G-D identified as the cell adhesion site of fibronectin, vitronectin,vWf, and the α chain of human fibrinogen. Therefore, synthetic peptidescontaining the R-G-D sequence cause detachment of endothelial cells fromthe extracellular in matrix in vitro.

GP IIb/IIIa Antagonists

The final obligatory step in platelet aggregation is the binding offibrinogen to an activated membrane-bound glycoprotein complex, GPIIb/IIIa. Platelet activators such as thrombin, collagen, epinephrine orADP, are generated as an outgrowth of tissue damage. During activation,GP Ilb/IlIa undergoes changes in conformation that results in exposureof occult binding sites for fibrinogen. There are six putativerecognition sites within fibrinogen for GP IIb/IIIa and thus fibrinogencan potentially act as a hexavalent ligand to crossing GP IIb/IIIamolecules on adjacent platelets. A deficiency in either fibrinogen or GPIIb/IIIa a prevents normal platelet aggregation regardless of theagonist used to activate the platelets. Since the binding of fibrinogento its platelet receptor is an obligatory component of normalaggregation, GP IIb/IIIa is an attractive target for an antithromboticagent.

Results from clinical trials of GP IIb/IIIa inhibitors support thishypothesis. The monoclonal antibody 7E3, which blocks the GP IIb/IIIareceptor, has been shown to be an effective therapy for the high riskangioplasty population. It is used as an adjunct to percutaneoustransluminal coronary angioplasty or atherectomy for the prevention ofacute cardiac ischemic complications in patients at high risk for abruptclosure of the treated coronary vessel. Although 7E3 blocks both theIIb/IIIa receptor and the α_(v)β₃ receptor, its ability to inhibitplatelet aggregation has been attributed to its function as a IIb/IIIareceptor binding inhibitor.

A study reported in The New England Journal of Medicine vol. 330, No.14, pp. 956-961 (1994) showed a decrease from 12.8% to 8.3% in thecombined endpoints of death, non-fatal myocardial infarction (MI) andneed for urgent revascularization with fibrinogen receptor blockade.This benefit was at the expense of some additional risk of bleeding,with the need for transfusion increasing from 3% to 6%, and theincidence of patients with decreased hematocrit increasing from 7% to15%. 7E3 was added to the standard regime of heparin and aspirin thusleaving few hemostatic control mechanisms intact. The clinical benefitsof this drug could be seen at 6 months.

Many other studies have shown that blocking the GP IIb/IIIa receptorwill stop platelet aggregation induced by all of the agonists and thusprevent thrombus formation but leave platelet adhesion relativelyintact. The 7E3 monoclonal antibody is described in Coller et al., Ann.NY Acad. Sci. 1991; 614:193-213; and Coller et al., J. Clin Invest.1985; 76:101-108. Others have used agents based on the RGD sequence,including snake venom proteins, small peptides, and peptidomimetics(Cook et al., Drugs of Future, 1994; 19:135-159; and Cox et al.,Medicinal Research Reviews, 1994; 14:195-228).

The snake venom proteins, termed disintegrins, have provided importantstructural information, but their antigenicity has limited theirdevelopment as therapeutic agents (Cook et al., ibid.; and Cox et al.,ibid.). Integrelin (also known as INTEGRILIN™) is a cyclic peptide thatis based on the KGD sequence in the snake venom protein barbourin (Cooket al., ibid.; and Cox et al., ibid.). It inhibits ligand binding to GPIIb/IIIa but has very little effect on ligand binding to α_(v)β₃. Amongthe non-peptide compounds are Ro 44-9883 and MK-383, which areadministered intravenously, and are also selective for GP IIb/IIIa (Cooket al., ibid.; and Cox et al., ibid.). Orally active agents includeSC54684, which is a prodrug (i.e., it requires biotransformation in vivoto its active form) with high oral bioavailability and Ro 43-8857,GR144053, and DMP728, which are themselves the active inhibitors (Cooket al., ibid.; and Cox et al., ibid.). Literally thousands of othercompounds have been synthesized in an attempt to obtain optimal potency,metabolic stability, receptor specificity, and favorable intravascularsurvival. Despite variations in these compounds, virtually of all ofthem when they are in their active form retain the basic chargerelations of the RGD sequence with a positive charge separated from anegative charge by approximately 10-20 Å(Cook et al., ibid.; and Cox etal., ibid.).

Platelet aggregation is profoundly inhibited when increasingconcentrations of murine 7E3 or c7E3 Fab are added to platelet-richplasma in vitro or administered in incremental doses to animals orhumans in vivo (Coller et al., Ann. NY Acad., ibid.; Tcheng et al.,ibid.; and Simoons et al., Circulation 1994; 89:596-603). There is anexcellent correlation between the percentage of receptors blocked andthe inhibition of aggregation, with nearly complete inhibition ofaggregation when 80% or more of the receptors are blocked (Coller etal., Ann. NY Acad., ibid.).

The results of the 7E3 study support the hypothesis that blockade ofGPIIb/IIIa receptors is more effective than aspirin in preventingplatelet thrombi, even in the presence of heparin. They also support thehypothesis that platelet-dependent thrombi frequently contributesignificantly to the development of ischemic complications after PTCA,even when minor mechanical dissections are present.

It has been clear for several decades that elevated blood cholesterol isa major risk factor for coronary heart disease, and many studies haveshown that the risk of CHD events can be reduced by lipid-loweringtherapy. Prior to 1987, the lipid-lowering armamentarium was limitedessentially to a low saturated fat and cholesterol diet, the bile acidsequestrants (cholestyramine and colestipol), nicotinic acid (niacin),the fibrates and probucol. Unfortunately, all of these treatments havelimited efficacy or tolerability, or both. With the introduction oflovastatin, the first inhibitor of HMG-CoA reductase to become availablefor prescription in 1987, for the first time physicians were able toobtain large reductions in plasma cholesterol with very few adverseeffects.

Recent studies have unequivocally demonstrated that lovastatin,simvastatin and pravastatin, all members of the HMG-CoA reductaseinhibitor class, slow the progression of atherosclerotic lesions in thecoronary and carotid arteries. Simvastatin and pravastatin have alsobeen shown to reduce the risk of coronary heart disease events, and inthe case of simvastatin a highly significant reduction in the risk ofcoronary death and total mortality has been shown by the ScandinavianSimvastatin Survival Study. This study also provided some evidence for areduction in cerebrovascular events. Additional studies have shown thatHMG CoA RI's may have an effect on platelet aggregation.

Improved treatments for inhibiting platelet aggregation are currentlybeing sought for the large number of individuals who are at risk forreocclusion following thrombolytic therapy and angioplasty, transientischemic attacks and a variety of other vaso-occlusive disorders. Theinstant invention addresses this problem by providing a combinationtherapy comprised of a platelet aggregation inhibitor with an HMG-CoARI, and more particularly, a GP IIb/IIIa receptor antagonist with anHMG-CoA RI. When administered as part of a combination therapy, theplatelet aggregation inhibitor together with the HMG-CoA RI provideenhanced inhibition of platelet aggregation as compared toadministration of either the HMG-CoA RI or the platelet aggregationinhibitor alone. Due to the greater benefit of the drug combination,lesser dosage amounts of the platelet aggregation inhibitor, and moreparticularly the GP IIb/IIIa receptor antagonist, may be needed toachieve the desired clinical result, thereby resulting in improvedsafety.

SUMMARY OF THE INVENTION

One object of the instant invention is to provide a novel combinationtherapy comprised of a therapeutically effective amount of a cholesterolreducing agent such as an HMG-CoA reductase inhibitor in combinationwith a platelet aggregation inhibitor which is useful for inhibitingplatelet aggregation and for inhibiting the formation of thromboticocclusions in mammals. The instant invention further provides novelmethods for treating, preventing and reducing the risk of occurrence ofcardiovascular and cerebrovascular events and related vaso-occlusivedisorders. Another object of this invention is to provide pharmaceuticalcompositions which can be used with the above-described methods. Afurther object is to provide a kit comprised of an HMG-CoA reductaseinhibitor composition and a platelet aggregation inhibitor composition.Additional objects will be evident from the following detaileddescription.

DETAILED DESCRIPTION OF THE INVENTION

The instant invention involves a novel combination therapy comprisingthe administration of a therapeutically effective amount of an HMG-CoARI in combination with a therapeutically effective amount of a plateletaggregation inhibitor to a mammal, and more particularly, to a human.The combination therapy is used to inhibit platelet aggregation inmammals who are in need of such inhibition, and to prevent or treatdisorders related to platelet aggregation.

The instant invention also provides pharmaceutical compositionscomprised of a therapeutically effective amount of an HMG-CoA RI incombination with a therapeutically effective amount of a plateletaggregation inhibitor and a pharmaceutically acceptable carrier. Oneembodiment of the instant compositions is a single composition adaptedfor oral administration comprised of a therapeutically effective amountof an HMG-CoA RI in combination with a therapeutically effective amountof a platelet aggregation inhibitor and a pharmaceutically acceptablecarrier.

A compound which inhibits HMG-CoA reductase is used in combination witha platelet aggregation inhibitor to practice the instant invention.Examples of HMG-CoA reductase inhibitors that may be used include butare not limited to lovastatin (MEVACOR®; see U.S. Pat. No. 4,231,938),simvastatin (ZOCOR®; see U.S. Pat. No. 4,444,784), pravastatin(PRAVACHOL®; see U.S. Pat. No. 4,346,227), fluvastatin (LESCOL®; seeU.S. Pat. No. 5,354,772), atorvastatin (LIPITOR®; see U.S. Pat. No.5,273,995) and cerivastatin (also known as rivastatin; see U.S. Pat. No.5,177,080). The structural formulas of these and additional HMG-CoAreductase inhibitors that may be used in the instant methods aredescribed at page 87 of M. Yalpani, “Cholesterol Lowering Drugs”,Chemistry & Industry, pp. 85-89 (Feb. 5, 1996). Preferably, the HMG-CoARI is selected from lovastatin and simvastatin.

The term HMG-CoA reductase inhibitor is intended to include allpharmaceutically acceptable salt, ester and lactone forms of compoundswhich have HMG-CoA reductase inhibitory activity, and therefore the useof such salts, esters and lactone forms is included within the scope ofthis invention.

Compounds which have inhibitory activity for HMG-CoA reductase can bereadily identified by using assays well-known in the art. For example,see the assays described or cited in U.S. Pat. No. 4,231,938 at col. 6,and WO 84/02131 at pp. 30-33.

A compound which inhibits platelet aggregation is used in combinationwith an HMG-CoA reductase inhibitor to practice the instant invention.In one embodiment of the instant invention, the compound which inhibitsplatelet aggregation is an antagonist for the glycoprotein IIb/IIIafibrinogen receptor. Examples of glycoprotein IIb/IIIa receptorantagonists are described in U.S. Pat. No.'s 5,470,849, 5,463,011,5,455,243, 5,451,578, 5,446,056, 5,441,952, 5,422,249, 5,416,099,5,405,854, 5,397,791, 5,393,760, 5,389,631, 5,380,713, 5,374,622,5,358,956, 5,344,783, 5,340,798, 5,338,723, 5,334,596, 5,321,034,5,318,899 (e.g. cyclic heptapeptides such asMpr-(Acetimidyl-Lys)-Gly-Asp-Trp-Phe-Cys-NH₂,Mpr-(Acetimidyl-Lys)-Gly-Asp-Trp-Phe-Pen-NH₂,Mpr-(Phenylimidyl-Lys)-Gly-Asp-Trp-Phe-Pen-NH₂, andMpr-(Phenylimidyl-Lys)-Gly-Asp-Trp-Phe-Cys-NH₂, wherein Mpr is mercaptopropionyl), U.S. Pat. No. 5,312,923, 5,294,616, 5,292,756, 5,281,585,5,272,158, 5,264,420, 5,260,307, 5,239,113 (e.g. ethyl3-[[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4-pentynoate),U.S. Pat. No. 5,227,490, 5,206,373, 4,703,036 (e.g.N-Methyl-D-phenylalanyl-N-[(1S)-1-formyl-4-guanidinobutyl]-L-prolinamide); European Patent publication No.'s EP505 868 (e.g.,((1-(2-((4-(aminoiminomethyl)benzoyl)amino)-3-(4-hydroxyphenyl)-1-oxopropyl)-4-piperidinyl)oxy)-(S)-acetic acid), EP 333 356, and EP 656348; and International Publication No.'s WO 93/11152 (e.g.,N-(2-(2-(((3-((aminoiminomethyl)amino)propyl)amino)-carbonyl)-1-piperidnyl)-1-(cyclohexylmethyl)-2-oxoethyl)-(R,S)-glycine),WO 94/18981, WO 94/22820, WO 95/14683, and WO 97/15568, all of which areherein incorporated by reference, and wherein the scope of thisinvention includes, but is not limited to, the use of each of thespecifically disclosed compounds therein. They are described as usefulfor inhibiting fibrinogen binding and inhibiting clot formation.

In particular, the GP IIb/IIIa receptor antagonist is selected from thefollowing compounds and the pharmaceutically acceptable salts, esters,and solvates (including hydrates) thereof:[3(R)-[2-piperidin-4-yl)ethyl]-2-piperidone-1]acetyl-3(R)-methyl-β-alanine described in U.S. Pat. No. 5,281,585,(see compound 57 in column 67) and referred to herein as Compound A:

5-[(4-Piperidinyl)methoxy]-2-indolecarbonyl-2(S)-phenylsulfonyl-amino-β-alaninedescribed in WO 97/15568 at page 20 as compound 2-6, and referred toherein as Compound B:

2(S)-[(p-Toluenesulfonyl)amino]-3-[[[5,6,7,8-tetrahydro-4-oxo-5-[2-(piperidin-4-yl)ethyl]-4H-pyrazolo-[1,5-a][1,4]diazepin-2-yl]carbonyl]-amino]propionic acid described in WO 94/18981,and referred to herein as Compound C:

MK-383(2-S-(n-Butylsulfonylamino)-3[4-piperidin-4-yl)butyloxyphenyl]propionicacid hydrochloride, and also known as tirofiban) described in U.S. Pat.No. 5,292,756; DMP 728; DMP 754((R)-methyl-3-[[[3-[4-(aminoiminomethyl)phenyl]-4,5-dihydro-5-isoxazolyl]acetyl]amino]-N-(butoxycarbonyl)-L-alaninemonoacetate) from DuPont-Merck, described in WO 95/14683 and inTetrahedron Letters, 1996, 37 :4455-4458:

Ro44-9883, Ro43-8857 and Ro48-3657 (acetic acid,[[1-[2-[[4-[amino(hydroxyimino)methyl]benzoyl]amino]-1-oxopropyl]-4-piperidinyl]oxy]-,ethyl ester, and also known as sibrafiban) from Hoffman-LaRoche;sibrafiban and related compounds are described in EP 656 348:

xemlofiban (ethyl3-[[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4-pentynoate,also known as xemilofiban and SC-54684), particularly the HCl saltthereof, described in U.S. Pat. No.'s 5,344,957 and 5,239,113:

fradafiban((3S,5S)-5-[[(4′-Amidino-4-biphenyl)oxy]methyl]-2-oxo-3-pyrrolidineaceticacid, also known as BIBU-104) as described in U.S. Pat. No. 5,541,343assigned to Thomae:

orbofiban(N-[[(3S)-1-(p-Amidinophenyl)-2-oxo-3-pyrrolidinyl-carbamoyl]-β-alanine,ethyl ester), particularly the monoacetate and monoacetate hydrate formsthereof, as described in U.S. Pat. No. 5,484,946 assigned to Searle:

SB 214857((−)-(S)-2-[7-(4,4′-Bipiperidin-1-ylcarbonyl)-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-yl]aceticacid) from SmithKline Beecham, as described in WO 95/18619; ZD-2486((R)-3-Methyl-4-[4-[4-(4-pyridyl)piperazin-1-yl]phenoxy]butyric acid)from Zeneca, as described in U.S. Pat. No.'s 5,556,977 and 5,563,141;TAK-029 from Takeda; RPR 109891 from Rhone Polenc Rorer; GR144053 fromGlaxo; GR233548 from Glaxo; and SDZ 562 from Sandoz.

The compounds MK-383, DMP 728, Ro44-9883, Ro43-8857, SC-54684 andGR144053 are described in Cook et al., Drugs of the Future, 1994,19(2):135-159, and Cox et al., Medicinal Research Reviews, 1994, 14:195-228. DMP 728 is also described in Circulation, 1996, 93 :537-543;and GR144053 is also described in Thrombosis and Hematosis, 1993, 69:1071. TAK 029 is described in J. Pharmacology and ExperimentalTherapeutics, 1996, 277 :502-510. Xemlofiban is described inCirculation, 1995, 92 :2331.

More particularly, the GP IIb/IIIa receptor antagonist is selected fromCompound A, Compound B, and DMP 754, which are all orally availablecompounds. Most particularly, the GP IIb/IIIa receptor antagonist is DMP754.

One test which is used to evaluate fibrinogen IIb/IIIa receptorantagonist activity is based on evaluation of inhibition ofADP-stimulated platelets. Aggregation requires that fibrinogen bind toand occupy the platelet fibrinogen receptor site. Inhibitors offibrinogen binding inhibit aggregation. In the ADP-stimulated plateletaggregation assay, human platelets are isolated from fresh blood,collected into acid citrate/dextrose by differential centrifugationfollowed by gel filtration on Sepharose 2B in divalent ion-free Tyrode'sbuffer (pH 7.4) containing 2% bovine serum albumin.

Platelet aggregation is measured at 37° C. in a Chronolog aggregometer.The reaction mixture contains gel-filtered human platelets (2×10⁸ perml), fibrinogen (100 micrograms per ml (ug/ml)), Ca²⁺ (1 mM), and thecompound to be tested. The aggregation is initiated by adding 10 mM ADP1 minute after the other components are added. The reaction is thenallowed to proceed for at least 2 minutes. The extent of inhibition ofaggregation is expressed as the percentage of the rate of aggregationobserved in the absence of inhibitor. The IC₅₀ is the dose of aparticular compound inhibiting aggregation by 50% relative to a controllacking the compound.

Compounds which are selective GP IIb/IIIa receptor antagonists may beemployed in the instant invention, as well as compounds which block boththe GP IIb/IIIa receptor and the α_(v)β₃ vitronectin receptor, such asthe monoclonal antibody 7E3. Compounds which are selective for theglycoprotein IIb/IIIa receptor are those having a preference (e.g.10-fold) for binding to IIb/IIIa as compared to other receptors of theintegrin family (e.g. α_(v)β₃, α₅β₁, α_(v)β_(v)β₅). Selectivity of thesecompounds can be readily determined by persons skilled in the art.

In another embodiment of this invention, the compound which inhibitsplatelet aggregation is one that blocks ADP induced plateletaggregation. Examples of such compounds include ticlopidine (TICLID®),and clopidogrel (PLAVIX®).

In a further embodiment of this invention, the compound which inhibitsplatelet aggregation is selected from aspirin and dipyridamole.

Herein, the term platelet aggregation inhibitor (or inhibitor ofplatelet aggregation) is intended to include all pharmaceuticallyacceptable salt, ester and solvate forms, including hydrates, ofcompounds which have platelet aggregation inhibitory activity as well aspro-drug forms. Such pro-drugs are compounds which do not have plateletaggregation inhibitory activity outside the body but become active asinhibitors after they are administered to the patient. Therefore the useof such salts, esters solvate forms and pro-drugs of plateletaggregation inhibitors is included within the scope of this invention.

Likewise, the term GP IIb/IIIa receptor antagonist is intended toinclude all pharmaceutically acceptable salt, ester and solvate forms,including hydrates, of compounds which have GP IIb/IIIa receptorantagonist activity as well as pro-drug forms. Such pro-drugs arecompounds which do not have GP IIb/IIIa receptor antagonist activityoutside the body but become active as antagonists after they areadministered to the patient. Therefore the use of such salts, esters,solvate forms and pro-drugs of GP IIb/IIIa receptor antagonists is alsoincluded within the scope of this invention. Pro-drug forms of IIb/IIIareceptor antagonists generally are not active antagonists until afterthey are metabolised in the body to the active drug form; such prodrugsmay be, but are not limited to, ester derivatives. Ester derivatives ofthe described compounds may act as prodrugs which, when absorbed intothe bloodstream of a warm-blooded animal, may cleave in such a manner asto release the drug form and permit the drug to afford improvedtherapeutic efficacy. An example of such a pro-drug is Ro 48-3657.

Herein, the term “pharmaceutically acceptable salts” shall meannon-toxic salts of the compounds employed in this invention which aregenerally prepared by reacting the free acid with a suitable organic orinorganic base. Examples of such salts include, but are not limited to,acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,borate, bromide, calcium edetate, camsylate, carbonate, chloride,clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate,esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynapthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,oleate, oxalate, pamaote, palmitate, panthothenate,phosphate/diphosphate, polygalacturonate, salicylate, sodium, stearate,subacetate, succinate, tannate, tartrate, teoclate, tosylate,triethiodide, valerate.

The terms “active agent(s)” and “active drug(s)” are used herein as away to refer to both the HMG-CoA reductase inhibitors and the plateletaggregation inhibitors which are employed in the instant methods andcompositions. Both terms are intended to encompass all salt, ester andpro-drug forms of HMG-CoA reductase inhibitors and platelet aggregationinhibitors, even where the pro-drug form is not active itself but isconverted to the active drug form after administration.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients, in specified amounts whereamounts are specified, as well as any product which results directly orindirectly from combination of the specified ingredients, in thespecified amounts where amounts are specified.

As used herein, the term “myocardial infarction” is intended to includeboth Q-wave and non-Q-wave myocardial infarction, unless otherwisenoted.

The instant method involves the administration of an HMG-CoA reductaseinhibitor in combination with a platelet aggregation inhibitor. Thiscombination therapy includes administration of a single phannaceuticaldosage formulation which contains both the HMG-CoA reductase inhibitorand the platelet aggregation inhibitor, as well as administration ofeach active agent in its own separate pharmaceutical dosage formulation.While the HMG-CoA reductase inhibitor can be administered orally orparenterally, oral dosing is preferred. The GP IIb/IIIa receptorantagonist can be administered orally, intravenously, transdermally (forexample using an iontophoretic patch), intraocularly, intranasally or byother routes known to those skilled in the medical arts, taking intoaccount that certain GP IIb/IIIa receptor antagonists are developed fororal administration while others may be developed for non-oral routessuch as intravenous administration. Ticlopidine, clopidogrel, aspirinand dipyridamole are administered orally. Preferably, both active agentsof the instant combination therapy are administered orally, and mostpreferably the active agents are combined in a single oral dosageformulation.

For example, a GP IIb/IIIa receptor antagonist and an HMG-CoA reductaseinhibitor can be administered to the patient together in one oralcomposition such as a tablet or capsule. Another example would be asingle oral composition comprised of aspirin and an HMG-CoA reductaseinhibitor. Alternatively, the combination therapy may compriseadministration of an oral HMG-CoA reductase inhibitor composition with aseparate oral aspirin composition, or with a separate GP IIb/IIIareceptor antagonist composition formulated for oral, intravenous,transdermal, intraocular, or intranasal administration.

Where separate dosage formulations are used, the HMG-CoA reductaseinhibitor and the platelet aggregation inhibitor can be administered atessentially the same time, i.e., concurrently, or at separatelystaggered times, i.e, sequentially. Similarly, a GP IIb/IIIa receptorantagonist may be administered on an intravenous regimen, while thepatient is orally dosed once a day with a conventional orcontrolled-release formulation of an HMG-CoA reductase inhibitor.Combination therapy is understood to include all these regimens.Administration in these various ways are suitable for the presentinvention as long as the beneficial pharmaceutical effect of theplatelet aggregation inhibitor and HMG-CoA reductase inhibitor arerealized by the patient at substantially the same time. Such beneficialeffect is achieved when the target blood level concentrations of eachactive drug are maintained at substantially the same time. Concurrentoral administration is preferred.

It is expected that a combination therapy of intravenously administeredGP IIb/IIIa receptor antagonist with orally administered HMG-CoAreductase inhibitor could be used in response to an acute medical eventwhere inhibition of platelet aggregation is needed, and may generally beadministered for a period of time of one or two weeks or up to a monthor longer if deemed necessary. Where the combination therapy involvesfor example oral administration of both the GP IIb/IIIa receptorantagonist and the HMG-CoA reductase inhibitor, the therapy may beadministered on a longer-term chronic basis, such as a period of severalmonths or years, for as long as deemed medically appropriate for thepatient.

Therapeutically effective amounts of the platelet aggregation inhibitorsand the HMG-CoA reductase inhibitors are suitable for use in thecompositions and methods of the present invention. The term“therapeutically effective amount” is intended to mean that amount of adrug or pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, a system, animal or human that is being sought bya researcher, veterinarian, medical doctor or other clinician. Thedosage regimen utilizing an HMG-CoA RI in combination with a plateletaggregation inhibitor is selected in accordance with a variety offactors including type, species, age, weight, sex and medical conditionof the patient; the severity of the condition to be treated; the routeof administration; the renal and hepatic function of the patient; andthe particular compound or salt or ester thereof employed. Since twodifferent active agents are being used together in a combinationtherapy, the potency of each of the agents and the enhanced effectsachieved by combining them together must also be taken into account. Aconsideration of these factors is well within the purview of theordinarily skilled clinician for the purpose of determining thetherapeutically effective amounts of the drug combination needed toprevent, counter, or arrest the progress of the condition.

Dosage information for HMG-CoA RI's is well known in the art, sinceseveral HMG-CoA RI's are marketed in the U.S. In particular, the dailydosage amounts of the HMG-CoA reductase inhibitor may be the same orsimilar to those amounts which are employed foranti-hypercholesterolemic treatment and which are described in thePhysicians' Desk Reference (PDR). For example, see the 50^(th) Ed. ofthe PDR, 1996 (Medical Economics Co); in particular, see at page 216 theheading “Hypolipidemics,” sub-heading “HMG-CoA Reductase Inhibitors,”and the reference pages cited therein. Preferably, the oral dosageamount of HMG-CoA RI is from about 1 to 200 mg/day, and more preferablyfrom about 5 to 160 mg/day. However, dosage amounts will vary dependingon the potency of the specific HMG-CoA reductase inhibitor used as wellas other factors as noted above. Also, the dosage amount of HMG-CoAreductase inhibitor needed to achieve the desired effect will beaffected by the dosage amount and potency of the IIb/IIIa receptorantagonist or other platelet aggregation inhibitor which is employed inthe combined therapy. An HMG-CoA RI which has sufficiently greaterpotency may be given in sub-milligram daily dosages.

As examples, the daily dosage amount for simvastatin may be selectedfrom 5 mg, 10 mg, 20 mg, 40 mg, 80 mg and 160 mg; for lovastatin, 10 mg,20 mg, 40 mg and 80 mg; for fluvastatin sodium, 20 mg, 40 mg and 80 mg;and for pravastatin sodium, 10 mg, 20 mg, and 40 mg. The daily dosageamount for atorvastatin calcium may be in the range of from 1 mg to 160mg, and more particularly from 5 mg to 80 mg, including dosage amountsof 10 mg, 20 mg and 40 mg. Oral administration may be in single ordivided doses of two, three, or four times daily, although a singledaily dose of the HMG-CoA RI is preferred.

Oral dosages of GP IIb/IIIa receptor antagonists when used for theindicated effects, will range between about 0.001 mg per kg of bodyweight per day (mg/kg/day) to about 50 mg/kg/day and preferably 0.005-20mg/kg/day and most preferably 0.005-10 mg/kg/day. Suitable oral tabletsand capsules contain between 0.1 mg and 5 g, preferably between 0.5 mgand 2 g, most preferably between 0.5 mg and 1 g, for example, 0.5 mg, 1mg, 5 mg, 10 mg, 50 mg, 150 mg, 250 mg, or 500 mg of GP IIb/IIIareceptor antagonist. Oral administration may be in one or divided dosesof two, three, or four times daily. A single daily dose is preferred.

Intravenously, the most preferred doses for GP IIb/IIIa receptorantagonists will range from about 0.5 μpg to about 5 mg/kg/minute duringa constant rate infusion, to achieve a plasma level concentration duringthe period of time of administration of between 0.1 ng/ml and 1 μg/ml.

Dosage amounts for ticlopidine are described in the Physicians' DeskReference. Dosage amounts of aspirin for the indicated effects are knownto those skilled in medical arts, and generally range from about 75 mgto about 325 mg per day. For example, a formulation may contain 75 mg,80 mg, 160 mg, 250 mg, or 325 mg of aspirin.

Suitable oral formulations of clopidogrel may contain from 25 mg to 500mg, preferably from 75 mg to 375 mg, and most preferably from 75 mg to150 mg of clopidogrel. For example, the formulation may contain 25 mg,50 mg, 75 mg, 150 mg, 250 mg, or 500 mg of clopidogrel. Oraladministration may be in one or divided doses of two, three, or fourtimes daily. A single daily dose is preferred.

The active agents employed in the instant combination therapy can beadministered in such oral forms as tablets, capsules (each of whichincludes sustained release or timed release formulations), pills,powders, granules, elixirs, tinctures, suspensions, syrups, andemulsions. The instant invention includes the use of both oralrapid-release and time-controlled release pharmaceutical formulations(see, e.g., U.S. Pat. No. 5,366,738 which describes controlled releaseformulations). Suitable intravenous compositions for the GP IIb/IIIareceptor antagonists include bolus or extended infusion. Such oral andintravenous compositions are known to those of ordinary skill in thepharmaceutical arts. For example, see Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa.

The active drugs can be administered in admixture with pharmaceuticaldiluents, excipients or carriers (collectively referred to herein as“carrier” materials) suitably selected with respect to the intended formof administration, that is, oral tablets, capsules, elixirs, syrups andthe like, and consistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with a non-toxic,pharmaceutically acceptable, inert carrier such as lactose, starch,sucrose, glucose, modified sugars, modified starches, methyl celluloseand its derivatives, dicalcium phosphate, calcium sulfate, mannitol,sorbitol and other reducing and non-reducing sugars, magnesium stearate,steric acid, sodium stearyl fumarate, glyceryl behenate, calciumstearate and the like. For oral administration in liquid form, the drugcomponents can be combined with non-toxic, pharmaceutically acceptableinert carrier such as ethanol, glycerol, water and the like. Moreover,when desired or necessary, suitable binders, lubricants, disintegratingagents and coloring and flavoring agents can also be incorporated intothe mixture. Stabilizing agents such as antioxidants (BHA, BHT, propylgallate, sodium ascorbate, citric acid) can also be added to stabilizethe dosage forms. Other suitable components include gelatin, sweeteners,natural and synthetic gums such as acacia, tragacanth or alginates,carboxymethylcellulose, polyethylene glycol, waxes and the like.

The active drugs can also be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, such as cholesterol, stearylamine orphosphatidylcholines.

Active drug may also be delivered by the use of monoclonal antibodies asindividual carriers to which the compound molecules are coupled. Activedrug may also be coupled with soluble polymers as targetable drugcarriers. Such polymers can include polyvinyl-pyrrolidone, pyrancopolymer, polyhydroxy-propyl-methacrylamide-phenol,polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, active drug may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid, polyglycolicacid, copolymers of polylactic and polyglycolic acid, polyepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates and cross linked or amphipathicblock copolymers of hydrogels.

The compositions and methods of the present invention may be used astreatment for acute cardiovascular and cerebrovascular events, as wellas for chronic therapy for prevention or reduction of risk of occurrenceof cardiovascular and cerebrovascular events. For example, thecompositions of this invention, and methods for administering thecombination therapy of a platelet aggregation inhibitor with an HMG-CoAreductase inhibitor, are useful for treating, preventing or reducing therisk of occurrence of acute coronary ischemic syndrome in mammals, andmore particularly in humans, who are at risk of developing acutecoronary ischemic syndrome. Acute coronary ischemic syndrome includesthe conditions of unstable angina and non-Q-wave myocardial infarction.

Compositions and methods of the invention may be used to prevent orreduce the risk of formation of thrombi and thromboemboli and thereforeto prevent or reduce the risk of thrombotic occlusions and reocclusions.They are useful in surgery on peripheral arteries (arterial grafts,carotid endaterectomy) and in cardiovascular surgery where manipulationof arteries and organs, and/or the interaction of platelets withartificial surfaces, leads to platelet aggregation and potentialformation of thrombi and thromboemboli. For example, the combinationtherapy can be used for preventing or reducing the risk of occurrence ofplatelet thrombosis, thromboembolism and reocclusion after acuteintervention such as atherectomy, angioplasty (PTCA), coronary arterybypass procedures or cardiac valve replacement. The combination therapycan also be used for preventing or reducing the risk of occurrence ofplatelet thrombosis, thromboembolism and reocclusion during and afterthrombolytic therapy. Since blood vessels can also sustain chronicdamage by the pathophysiological processes of atherosclerosis, patientswith atherosclerosis can also be treated with the instant combinationtherapy to prevent or reduce the risk of occlusive thrombus formation.The instant combination therapy can be used to treat, prevent or reducethe risk of intermittent claudication, which is a clinical manifestationof peripheral vessel disease. Combination therapy of an HMG-CoAreductase inhibitor with a GP IIb/IIIa receptor antagonist may reducethe risk of thrombocytopenia.

The instant combination therapy can also be used to treat, prevent orreduce the risk of a first or subsequent Q-wave myocardial infarction inpersons at risk for such events as well as to prevent or reduce the riskof restenosis in persons at risk for restenosis. Additionally, theinstant combination therapy can be used for treating, preventing orreducing the risk of occurrence of acute cerebrovascular ischemic eventssuch as a first or subsequent thrombotic stroke or transient ischemicattack. In general, the instant combination therapy can be used wheneverantiplatelet therapy, or inhibition of platelet aggregation, is needed.

The compositions and methods of the present invention are also useful incombination with procedures for treating patients with otheranticoagulants (e.g. thrombin inhibitors such as heparin and Factor Xainhibitors such as warfarin), and thrombolytic agents (e.g.streptokinase and tissue plasminogen activator). The instant combinationtherapy can also be co-adminstered with a β-adrenergic receptor blocker.In particular, a combination of an HMG-CoA RI with aspirin can beco-administered with a β-adrenergic receptor blocker to reduce the riskof coronary heart disease and cerebrovascular clinical events such asmyocardial infarction, stroke and cardiovascular death, particularly inpost-MI patients. Examples of β-adrenergic receptor blockers include butare not limited to acebutolol, atenolol, betaxolol, bioprolol,carteolol, labetalol, metoprolol, nadolol, penbutolol, pindolol,propanolol, and timolol. Dosage amounts of β-adrenergic receptorblockers are described in the PDR.

In accordance with this invention, a therapeutically effective amount ofan HMG-CoA RI and a therapeutically effective amount of a plateletaggregation inhibitor can be used for the preparation of a medicamentuseful for inhibiting platelet aggregation, and for treating, preventingor reducing the risk of developing acute coronary ischemic syndrome inmammals, particularly in humans. Additionally, a therapeuticallyeffective amount of an HMG-CoA RI and a therapeutically effective amountof a platelet aggregation inhibitor can be used for the preparation of amedicament useful for preventing or reducing the risk of formation ofthrombi and thromboemboli, for preventing or reducing the risk ofthrombotic occlusions and reocclusions, for treating, preventing orreducing the risk of a first or subsequent myocardial infarction, forpreventing or reducing the risk of restenosis, for treating, preventingor reducing the risk of acute cerebrovascular ischemic events such as afirst or subsequent thrombotic stroke or transient ischemic attack, andfor halting or slowing the progression of atherosclerotic disease. Moreparticularly, a therapeutically effective amount of an HMG-CoA RI and atherapeutically effective amount of a platelet aggregation inhibitor canbe used together for the preparation of a medicament suitable for oraladministration which is useful for the above-described treatments.Similarly, a therapeutically effective amount of an HMG-CoA RI can beused for the preparation of a medicament for use in combination with atherapeutically effective amount of a platelet aggregation inhibitor,which is useful for the above-described treatments. Also, atherapeutically effective amount of a platelet aggregation inhibitor canbe used for the preparation of a medicament for use in combination witha therapeutically effective amount of an HMG-CoA RI, which is useful forthe above-described treatments.

An additional embodiment of the instant invention involves a kitcomprised of an HMG-CoA RI in an oral dosage formulation and a plateletaggregation inhibitor in a separate oral dosage formulation. Moreparticularly, the kit is comprised of an HMG-CoA RI selected from thegroup consisting of lovastatin, simvastatin, pravastatin, fluvastatin,atorvastatin and cerivastatin; and. the platelet aggregation inhibitoris selected from the group consisting of a GP IIb/IIIa receptorantagonist, ticlopidine, clopidogrel, aspirin and dipyridamole. In oneclass of this embodiment the HMG-CoA RI is selected from lovastatin andsimvastatin, and more particularly the HMG-CoA RI is simvastatin. In asecond class of this embodiment, the platelet aggregation inhibitor is aGP IIb/IIIa receptor antagonist selected from the group consisting ofCompound A, Compound B, and DMP 754. In a third class of thisembodiment, the platelet aggregation inhibitor is aspirin.

One example of this embodiment is a kit comprised of an oral dosageformulation of simvastatin and an oral dosage formulation of aspirin.The packaging for the kit could be designed and manufactured in avariety of ways. A preferred example is a blister package containingrows of a simvastatin tablet and an aspirin tablet placed side by sideon the same blister card, each of the two tablets in its own blisterbubble, with calendar or similar type markings on the card that conveyto the user that one “pair” of tablets (i.e., one simvastatin tablet andone aspirin tablet) is to be ingested per day. A kit containingsimvastatin and a GP IIb/IIIa receptor antagonist such as Compound A,Compound B, or DMP 754 could be designed in a similar fashion.

A further class of this embodiment involves the kit described abovefurther comprising an oral dosage formulation of a pharmaceuticallyactive agent selected from a β-adrenergic receptor blocker and anangiotensin II receptor antagonist, in addition to the HMG-CoA RI andthe platelet aggregation inhibitor. More particularly, β-adrenergicreceptor blockers without intrinsic sympathomimetic activity (ISA) andwithout alpha blocking properties have a cardioprotective effect forpatients who have had a myocardial infarction and can be employed in thekit. Atenolol, metoprolol, betaxolol and acebutolol are beta blockerswithout ISA. Losartan potassium is currently marketed in the U.S. underthe trademark COZAAR®, and is one example of an angiotensin II receptorantagonist that could be employed in the kit. Dosages for beta blockersand for losartan potassium are commonly known to those skilled in thepharmaceuticalarts and can be found, for example in the Physician's DeskReference.

Examples of dosage formulations are as follows.

EXAMPLE 1 Tablet Preparation

Tablets containing simvastatin and a glycoprotein IIb/IIIa receptorantagonist can be prepared as illustrated below:

Ingredient Amount simvastatin   1 mg-200 mg. glycoprotein IIb/IIIareceptor antagonist 0.1 mg-5 g diluent binder disintegrant excipientsq.s. 200-400 mg. lubricant

EXAMPLE 2 Tablet Preparation

Tablets containing 25.0, 50.0, and 100.0 mg, respectively, of a GPIIb/IIIa receptor antagonist are prepared as illustrated below:

TABLE FOR DOSES CONTAINING FROM 25-100 MG OF GP IIB/IIIA RECEPTORANTAGONIST Amount-mg GP IIb/IIIa receptor 25.0 50.0 100.0 antagonistMicrocrystalline cellulose 37.25 100.0 200.0 Modified food corn starch37.25 4.25 8.5 Magnesium stearate 0.50 0.75 1.5

All of the active compound, cellulose, and a portion of the corn starchare mixed and granulated to 10% corn starch paste. The resultinggranulation is sieved, dried and blended with the remainder of the cornstarch and the magnesium stearate. The resulting granulation is thencompressed into tablets containing 25.0, 50.0, and 100.0 mg,respectively, of active ingredient per tablet.

EXAMPLE 3 Intravenous Formulations

An intravenous dosage form of the GP IIb/IIIa receptor antagonist isprepared as follows:

Amount GP IIb/IIIa receptor antagonist 0.5-10.0 mg Sodium Citrate 5-50mg Citric Acid 1-15 mg Sodium Chloride 1-8 mg Water for Injection (USP)q.s. to 1 L

Utilizing the above quantities, the active compound is dissolved at roomtemperature in a previously prepared solution of sodium chloride, citricacid, and sodium citrate in Water for Injection (USP, see page 1636 ofUnited States Pharmacopeia/National Formulary for 1995, published byUnited States Pharmacopeial Convention, Inc., Rockville, Md., copyright1994.

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various changes, modifications and substitutions can bemade therein without departing from the spirit and scope of theinvention. For example, effective dosages other than the particulardosages as set forth herein above may be applicable as a consequence ofvariations in the responsiveness of the mammal being treated for any ofthe indications for the active agents used in the instant invention asindicated above. Likewise, the specific pharmacological responsesobserved may vary according to and depending upon the particular activecompound selected or whether there are present pharmaceutical carriers,as well as the type of formulation and mode of administration employed,and such expected variations or differences in the results arecontemplated in accordance with the objects and practices of the presentinvention. It is intended, therefore, that the invention be defined bythe scope of the claims which follow and that such claims be interpretedas broadly as is reasonable.

What is claimed is:
 1. A method for reducing the risk of developing acondition selected from the group consisting of: acute coronary ischemicsyndrome, thrombosis, thromboembolism, thrombotic occlusion andreocclusion, restenosis, first or subsequent Q-wave myocardialinfarction, transient ischemic attack, and first or subsequentthrombotic stroke comprising administration of a therapeuticallyeffective amount of an HMG-CoA reductase inhibitor in combination with atherapeutically effective amount of a glycoprotein IIb/IIIa receptorantagonist to a mammal at risk of developing one or more of saidconditions.
 2. The method of claim 1 wherein the condition is acutecoronary ischemic syndrome.
 3. The method of claim 1 wherein thecondition is selected from thrombosis, thromboembolism, thromboticocclusion and reocclusion.
 4. The method of claim 1 wherein thecondition is restenosis.
 5. The method of claim 1 wherein the conditionis Q-wave myocardial infarction.
 6. The method of claim 1 wherein thecondition is transient ischemic attack.
 7. The method of claim 1 whereinthe condition is thrombotic stroke .
 8. A method for treating acardiovascular event selected from acute coronary ischemic syndrome andQ-wave myocardial infarction comprising administration of atherapeutically effective amount of an HMG-CoA reductase inhibitor incombination with a therapeutically effective amount of a glycoproteinIIb/IIIa receptor antagonist to a mammal in need of such treatment. 9.The method of claim 1 wherein the glycoprotein IIb/IIIa receptorantagonist and the HMG-CoA reductase inhibitor are both administeredorally.
 10. The method of claim 1 wherein the glycoprotein IIb/IIIareceptor antagonist and the HMG-CoA reductase inhibitor are administeredin a single oral dosage composition.
 11. The method of claim 1 whereinthe glycoprotein IIb/IIIa receptor antagonist is administeredintravenously and the HMG-CoA reductase inhibitor is administeredorally.
 12. The method of claim 1 wherein the glycoprotein IIb/IIIareceptor antagonist is selected from the group consisting of:Mpr-(Acetimidyl-Lys)-Gly-Asp-Trp-Phe-Cys-NH₂,Mpr-(Acetimidyl-Lys)-Gly-Asp-Trp-Phe-Pen-NH₂,Mpr-(Phenylimidyl-Lys)-Gly-Asp-Trp-Phe-Pen-NH₂,Mpr-(Phenylimidyl-Lys)-Gly-Asp-Trp-Phe-Cys-NH₂,N-Methyl-D-phenylalanyl-N-[(1S)-1-formyl-4-guanidinobutyl]-L-prolinamide,((1-(2-((4-(aminoiminomethyl)benzoyl)amino)-3-(4-hydroxyphenyl)-1-oxopropyl)-4-piperidinyl)oxy)-(S)-aceticacid,N-(2-(2-(((3-((aminoiminomethyl)amino)propyl)amino)carbonyl)-1-piperidnyl)-1-(cyclohexylmethyl)-2-oxoethyl)-(R,S)-glycine,Ethyl 3-[[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4-pentynoate,(2-S-(n-Butylsulfonylamino)-3[4-(piperidin-4-yl)butyloxyphenyl]propionicacid hydrochloride, and2(S)-[(p-Toluenesulfonyl)amino]-3-[[[5,6,7,8-tetrahydro-4-oxo-5-[2-(piperidin-4-yl)ethyl]-4H-pyrazolo-[1,5-a][1,4]diazepin-2-yl]carbonyl]-amino]propionicacid; and the pharmaceutically acceptable salts, esters and pro-drugsthereof.
 13. The method of claim 1 wherein the glycoprotein IIb/IIIareceptor antagonist is selected from the group consisting of: DMP 754,[3(R)-[2-piperidin-4-yl)ethyl]-2-piperidone-1]acetyl-3(R)-methyl-β-alanine, and5-[(4-Piperidinyl)methoxy]-2-indolecarbonyl-2(S)-phenylsulfonyl-amino-β-alanineand the pharmaceutically acceptable salts, esters and pro-drugs thereof.14. The method of claim 13 wherein the glycoprotein IIb/IIIa receptorantagonist is DMP754 and the pharmaceutically acceptable salts, estersand pro-drugs thereof.
 15. The method of claim 1 wherein the HMG-CoAreductase inhibitor is selected from the group consisting of lovastatin,simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin andthe pharmaceutically acceptable lactone, salt and ester forms thereof.16. The method of claim 15 wherein the HMG-CoA reductase inhibitor isselected from the group consisting of lovastatin and simvastatin and thepharmaceutically acceptable salts and esters thereof.
 17. A method forpreventing or reducing the risk of occurrence of acute coronary ischemicsyndrome and acute cerebrovascular ischemic events in patients at riskfor said occurrences comprising inhibiting the binding of fibrinogen tothe glycoprotein IIb/IIIa receptor and inhibiting the activity ofHMG-CoA reductase.
 18. A pharmaceutical composition comprising aglycoprotein IIb/IIIa receptor antagonist, an HMG-CoA reductaseinhibitor and a pharmaceutically acceptable carrier.
 19. The compositionof claim 18 wherein the HMG-CoA reductase inhibitor is selected fromlovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin,cerivastatin and the pharmaceutically acceptable lactone, salt and esterforms thereof.
 20. The composition of claim 19 wherein the HMG-CoAreductase inhibitor is selected from lovastatin and simvastatin and thepharmaceutically acceptable salts and esters thereof.
 21. Thecomposition of claim 18 wherein the glycoprotein IIb/IIIa receptorantagonist is selected from the group consisting of:Mpr-(Acetimidyl-Lys)-Gly-Asp-Trp-Phe-Cys-NH₂,Mpr-(Acetimidyl-Lys)-Gly-Asp-Trp-Phe-Pen-NH₂,Mpr-(Phenylimidyl-Lys)-Gly-Asp-Trp-Phe-Pen-NH₂,Mpr-(Phenylimidyl-Lys)-Gly-Asp-Trp-Phe-Cys-NH₂,N-Methyl-D-phenylalanyl-N-[(1S)-1-formyl-4-guanidinobutyl]-L-prolinamide,((1-(2-((4-(aminoiminomethyl)benzoyl)amino)-3-(4-hydroxyphenyl)-1-oxopropyl)-4-piperidinyl)oxy)-(S)-aceticacid,N-(2-(2-(((3-((aminoiminomethyl)amino)propyl)amino)carbonyl)-1-piperidnyl)-1-(cyclohexylmethyl)-2-oxoethyl)-(R,S)-glycine,Ethyl3-[[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4-pentynoate,(2-S-(n-Butylsulfonylamino)-3[4-(piperidin-4-yl)butyloxyphenyl]propionicacid hydrochloride, and2(S)-[(p-Toluenesulfonyl)amino]-3-[[[5,6,7,8-tetrahydro-4-oxo-5-[2-(piperidin-4-yl)ethyl]-4H-pyrazolo-[1,5-a][1,4]diazepin-2-yl]carbonyl]-amino]propionicacid; and the pharmaceutically acceptable salts, esters and pro-drugsthereof.
 22. The composition of claim 18 wherein the a glycoproteinIIb/IIIa receptor antagonist is selected from the group consisting of:DMP 754,[3(R)-[2-piperidin-4-yl)ethyl]-2-piperidone-1]acetyl-3(R)-methyl-β-alanine,and5-[(4-Piperidinyl)methoxy]-2-indolecarbonyl-2(S)-phenylsulfonyl-amino-β-alanineand the pharmaceutically acceptable salts, esters and pro-drugs thereof.23. The composition of claim 22 wherein the HMG-CoA reductase inhibitoris selected from lovastatin and simvastatin and the pharmaceuticallyacceptable salts and esters thereof.
 24. The composition of claim 18adapted for oral administration.
 25. A pharmaceutical composition madeby combining a glycoprotein IIb/IIIa receptor antagonist, an HMG-CoAreductase inhibitor and a pharmaceutically acceptable carrier.
 26. Aprocess for making a pharmaceutical composition comprising combining aglycoprotein IIb/IIIa receptor antagonist, an HMG-CoA reductaseinhibitor and a pharmaceutically acceptable carrier.
 27. The method ofclaim 1 wherein the glycoprotein IIb/IIIa receptor antagonist isselected from the group consisting of:[3(R)-[2-piperidin-4-yl)ethyl]-2-piperidone-1]acetyl-3(R)-methyl-β-alanine;5-[(4-Piperidinyl)methoxy]-2-indolecarbonyl-2(S)-phenylsulfonyl-amino-β-alanine;2(S)-[(p-Toluenesulfonyl)amino]-3-[[[5,6,7,8-tetrahydro-4-oxo-5-[2-(piperidin-4-yl)ethyl]-4H-pyrazolo-[1,5-a][1,4]diazepin-2-yl]carbonyl]-amino]propionicacid; MK-383; DMP 728; DMP 754; Ro44-9883; Ro43-8857; sibrafiban;xemlofiban; fradafiban; SB 214857; ZD-2486; TAK-029; orbofiban; RPR109891; GR144053; GR233548; and SDZ 562; and the pharmaceuticallyacceptable salts, esters and pro-drugs thereof.
 28. The composition ofclaim 18 wherein the glycoprotein IIb/IIIa receptor antagonist isselected from the group consisting of:[3(R)-[2-piperidin-4-yl)ethyl]-2-piperidone-1]acetyl-3(R)-methyl-β-alanine;5-[(4-Piperidinyl)methoxy]-2-indolecarbonyl-2(S)-phenylsulfonyl-amino-β-alanine;2(S)-[(p-Toluenesulfonyl)amino]-3-[[[5,6,7,8-tetrahydro-4-oxo-5-[2-(piperidin-4-yl)ethyl]-4H-pyrazolo-[1,5-a][1,4]diazepin-2-yl]carbonyl]-amino]propionicacid; MK-383; DMP 728; DMP 754; Ro44-9883; Ro43-8857; sibrafiban;xemlofiban; fradafiban; SB 214857; ZD-2486; TAK-029; orbofiban; RPR109891; GR144053; GR233548; and SDZ 562; and the pharmaceuticallyacceptable salts, esters and pro-drugs thereof.
 29. A kit comprised ofan HMG-CoA reductase inhibitor in an oral dosage formulation and aplatelet aggregation inhibitor in a separate oral dosage formulation.30. The kit of claim 29 wherein the HMG-CoA reductase inhibitor isselected from lovastatin and simvastatin, and the platelet aggregationinhibitor is a GP IIb/IIIa receptor antagonist.